The use of nanotechnologies to deliver therapeutic and diagnostic agents in a safer and more efficient manner to patients has led to an increased interest in the field during the last decades. Drug delivery systems, typically carriers such as liposomes, emulsions or micelles, intended to maximize the therapeutic efficacy of drugs thanks to the control of their biodistribution profile have emerged. Those systems offer the possibility to encapsulate a poorly soluble drug, to protect a drug from destruction or elimination, and/or to modify the blood circulation and distribution of a drug.
The observed rapid blood clearance of the first generation of drug delivery systems (DDSs) (due to their capture by the mononuclear phagocytic system (MPS)) has prompted the development of a second generation of DDSs exhibiting a surface modified by sterically stabilizing agents selected to bring “stealth” properties to the DDS when attached to its surface. These agents are typically flexible and/or hydrophilic polymers, such as polyethylene glycol (PEG) polymers and typically may bring surface charges that are slightly negative or positive. Steric stabilization prevents non-specific binding of the DDS's surface to blood components and reduce its rapid uptake and clearance in vivo by cells of the mononuclear phagocytic system (MPS), leading to prolonged DDS blood circulation times [Jain K. R. and Stylianopoulos T. Delivering nanomedicine to solid tumors. Nature Reviews. Clinical Oncology 2010, 7, 653-664]. Liposomal long-circulating nanoparticulate pharmaceutical drug delivery systems (NDDSs) are the most frequently studied type of NDDS; however, synthetic amphiphilic polymers have also been used to sterically stabilize other types of NDDS to alter their biodistribution [Torchilin V. P. Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery. Nature Reviews. Drug Discovery 2014, 13, 813-827].
Despite of this increased blood circulation time (i.e. enhanced blood transportation), which was thought as beneficial for the delivery of the therapeutic compound to its target site, the flexible and/or hydrophilic polymer coating, typically the PEG coating, was found to compromise the intracellular delivery of the pharmaceutical compound (i.e. the release of the compound at its target site), which ultimately resulted in a loss of activity for the delivery system. A way to overcome this limitation is to use cleavable PEG systems. However, the increase complexity in the design of such carriers may generate difficulties in the reproducibility of the carrier surface properties, resulting in batch-to batch unacceptable variability. Moreover, the extent of exposure of those “stealth” DDS has been related with more adverse events. DOXIL, a PEGylated liposomal formulation comprising doxorubicin, was for instance found to produce serious adverse events, such as the hand-foot syndrome or mucositis. The hydrophilic coating of the liposomes was questioned as perhaps facilitating their accumulation in ecerine sweat gland in palms and planta [Pegylated liposomal doxorubicin-related palmar-plantar erythrodysesthesia (‘hand-foot’ syndrome). D. Lorusso et al. Annals of Oncology. 2007; 18, 1159-1164].
WO2005/063305 relates to an assembly comprising a gas-filled microvesicle (with a size typically of at least 0.5 μm) and a component (with a size about below 100 nm) associated to said microvesicle. The resulting assembly is to be used as a pharmaceutically active component in diagnostically and/or therapeutically active formulations. The two components, i.e. the gas-filled microvesicle and the microvesicle associated component, are administered simultaneously typically for enhancing the imaging in the field of ultrasound contrast imaging, including targeted ultrasound imaging, ultrasound-mediated drug delivery and other imaging techniques.
As apparent from the prior art and despite of a long medical need, the safe and efficient delivery of pharmaceutical compounds (including therapeutic, prophylactic as well as diagnostic compounds) to their target site(s) remains a concern. There is a clear need to improve the compound's efficacy and safety, or in other words the pharmaceutic compound's transport and release, in order for said compound to reach its target site in a subject in the necessary and sufficient quantity to get the desired diagnostic, therapeutic or prophylactic effect.